The proposed studies are aimed at elucidating the molecular genetic bases of two inherited forms of low-renin childhood hypertension: apparent mineralocorticoid excess (AME; probably an autosomal recessive disorder) and dexamethasone-suppressible hyperaldosteronism (DSH; and autosomal dominant disorder). Patients with these disorders will be identified by detailed endocrinologic studies, and DNA samples from patients and family members will be obtained. In Specific Aim I, mutations in the gene encoding corticosteroid 11beta-dehydrogenase (11-DH) will be studied as a cause of AME. Sequence analysis of genomic clones encoding human 11-DH will be completed. Possible major deletions or rearrangements of the 11-DH genes in patients with AME will be detected by blot hybridization analysis of DNA samples. Small mutations in the 11-DH genes of patients will be identified by sequence analysis of cloned mutant genomic genes or of segments amplified by the polymerase chain reaction. The normal human 11- DH enzyme will be expressed from cDNA in cell culture, either by transfection of a plasmid containing a strong promoter or by infection of recombinant vaccinia virus. To determine the effects of each mutation detected in AME patients using in vitro mutagenesis and one of the above expression systems. If particular mutations are suspected to affected expression, normal and mutant promoter activities will be analyzed by ligating the promoters to an indicator gene and transfecting into a cell line expressing intrinsic 11-DH activity. In Specific Aim II, mutations in the steroid 11-hydroxylase (P450cll) gene (CYP11B1 and CYP11B2) will be studied as a possible cause of DSH. A linkage analysis of DSH will be carried out using P450cll cDNA and DNA samples from patients with DSH and their families. If CYP11B polymorphisms are not sufficiently informative the linkage analysis will be extended to additional polymorphic probes on chromosome 8q that flank CYP11B1 and B2. If the linkage analysis is consistent with the hypothesis that DSH is caused by a mutation in or near either of the CYP11B genes, mutant CYP11B genes from patients with DSH will be isolated and sequenced to identify each mutation. If missense mutations are identified, normal and mutant enzymes will be expressed in cell culture to determine the effect of each mutation on regulation of 18-oxidase activity.